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Signalling input from divergent pathways subverts B cell transformation.

ABSTRACT: Malignant transformation of cells typically involves several genetic lesions, whose combined activity gives rise to cancer¹. Here we analyse 1,148 patient-derived B-cell leukaemia (B-ALL) samples, and find that individual mutations do not promote leukaemogenesis unless they converge on one single oncogenic pathway that is characteristic of the differentiation stage of transformed B cells. Mutations that are not aligned with this central oncogenic driver activate divergent pathways and subvert transformation. Oncogenic lesions in B-ALL frequently mimic signalling through cytokine receptors at the pro-B-cell stage (via activation of the signal-transduction protein STAT5)^2-4 or pre-B-cell receptors in more mature cells (via activation of the protein kinase ERK)^5-8. STAT5- and ERK-activating lesions are found frequently, but occur together in only around 3% of cases (P = 2.2 × 10^-16). Single-cell mutation and phospho-protein analyses reveal the segregation of oncogenic STAT5 and ERK activation to competing clones. STAT5 and ERK engage opposing biochemical and transcriptional programs that are orchestrated by the transcription factors MYC and BCL6, respectively. Genetic reactivation of the divergent (suppressed) pathway comes at the expense of the principal oncogenic driver and reverses transformation. Conversely, deletion of divergent pathway components accelerates leukaemogenesis. Thus, persistence of divergent signalling pathways represents a powerful barrier to transformation, while convergence on one principal driver defines a central event in leukaemia initiation. Pharmacological reactivation of suppressed divergent circuits synergizes strongly with inhibition of the principal oncogenic driver. Hence, reactivation of divergent pathways can be leveraged as a previously unrecognized strategy to enhance treatment responses.

SUBMITTER: Chan LN

PROVIDER: S-EPMC7394729 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Signalling input from divergent pathways subverts B cell transformation.

Chan Lai N LN Murakami Mark A MA Robinson Mark E ME Caeser Rebecca R Sadras Teresa T Lee Jaewoong J Cosgun Kadriye Nehir KN Kume Kohei K Khairnar Vishal V Xiao Gang G Ahmed Mohamed A MA Aghania Eamon E Deb Gauri G Hurtz Christian C Shojaee Seyedmehdi S Hong Chao C Pölönen Petri P Nix Matthew A MA Chen Zhengshan Z Chen Chun Wei CW Chen Jianjun J Vogt Andreas A Heinäniemi Merja M Lohi Olli O Wiita Arun P AP Izraeli Shai S Geng Huimin H Weinstock David M DM Müschen Markus M

Nature 20200722 7818

Malignant transformation of cells typically involves several genetic lesions, whose combined activity gives rise to cancer<sup>1</sup>. Here we analyse 1,148 patient-derived B-cell leukaemia (B-ALL) samples, and find that individual mutations do not promote leukaemogenesis unless they converge on one single oncogenic pathway that is characteristic of the differentiation stage of transformed B cells. Mutations that are not aligned with this central oncogenic driver activate divergent pathways and ...[more]

PMID: 32699415

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Project description:The obligate intracellular pathogen, Anaplasma phagocytophilum, is the causative agent of human, equine, and canine granulocytic anaplasmosis and tick-borne fever (TBF) in ruminants. A. phagocytophilum has become an emerging tick-borne pathogen in the United States, Europe, Africa, and Asia, with increasing numbers of infected people and animals every year. It has been recognized that intracellular pathogens manipulate host cell metabolic pathways to increase infection and transmission in both vertebrate and invertebrate hosts. However, our current knowledge on how A. phagocytophilum affect these processes in the tick vector, Ixodes scapularis is limited. In this study, a genome-wide search for components of major carbohydrate metabolic pathways was performed in I. scapularis ticks for which the genome was recently published. The enzymes involved in the seven major carbohydrate metabolic pathways glycolysis, gluconeogenesis, pentose phosphate, tricarboxylic acid cycle (TCA), glyceroneogenesis, and mitochondrial oxidative phosphorylation and ?-oxidation were identified. Then, the available transcriptomics and proteomics data was used to characterize the mRNA and protein levels of I. scapularis major carbohydrate metabolic pathway components in response to A. phagocytophilum infection of tick tissues and cultured cells. The results showed that major carbohydrate metabolic pathways are conserved in ticks. A. phagocytophilum infection inhibits gluconeogenesis and mitochondrial metabolism, but increases the expression of glycolytic genes. A model was proposed to explain how A. phagocytophilum could simultaneously control tick cell glucose metabolism and cytoskeleton organization, which may be achieved in part by up-regulating and stabilizing hypoxia inducible factor 1 alpha in a hypoxia-independent manner. The present work provides a more comprehensive view of the major carbohydrate metabolic pathways involved in the response to A. phagocytophilum infection in ticks, and provides the basis for further studies to develop novel strategies for the control of granulocytic anaplasmosis.

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Signalling input from divergent pathways subverts B cell transformation.

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Signalling input from divergent pathways subverts B cell transformation.

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